The Synthesis of Quinestrol Analogues to Inhibit Cytochrome bd for the Treatment of Bacterial Infections

Antimicrobial Resistance (AMR) is a major global issue recognised by the World Health Organization as a threat to health and development worldwide. It has been responsible for more than 4.95 million deaths and is projected to cost healthcare systems US$1 trillion by 2050. Antibiotic resistance is a key component of AMR, with no new classes of antibiotics developed since the late 1980s, and many drugs becoming ineffective over the last 20 years. This thesis explores chemical modifications to quinestrol, an FDA-approved hormone replacement therapy (HRT) drug, which will be repurposed as an antibacterial agent to treat bacterial infections. The aim is to enhance the drug's potency while stabilising its structure during metabolism within the body. A series of chemical reactions were carried out to determine suitable reaction conditions, which were then used to synthesise chemical derivatives of quinestrol. These derivatives underwent biochemical analysis to evaluate their effectiveness against E. coli. The research identified a synthetic derivative of quinestrol with strong inhibitory effects against E. coli, with further metabolic stability testing to be conducted in future studies. Overall, this research highlights the importance of discovering new antibiotics with novel mechanisms of action to combat bacterial infections.